This invention relates to novel, aromatic compounds and pharmaceutically-acceptable salts thereof which possess useful pharmacological properties. More particularly the compounds of the invention are antagonists of the pain enhancing effects of E-type prostaglandins. The invention also relates to processes for the manufacture of the aromatic compounds and pharmaceutically-acceptable salts thereof; to novel pharmaceutical compositions containing them; and to use of the compounds in pain relief.
The compounds of the invention are useful in the treatment of pain such as the pain associated with joint conditions (such as rheumatoid arthritis and osteoarthritis), postoperative pain, post-partum pain, the pain associated with dental conditions (such as dental caries and gingivitis), the pain associated with burns (including sunburn), the treatment of bone disorders (such as osteoporosis, hypercalcaemia of malignancy and Paget""s disease), the pain associated with sports injuries and sprains and all other painful conditions in which E-type prostaglandins wholly or in part play a pathophysiological role.
Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates are the main classes of drugs in pain relief. However both possess undesireable side effects. NSAIDS are known to cause gastrointestinal irritation and opiates are known to be addictive.
We have now found a class of compounds structurally different to NSAIDS and opiates, and useful in the relief of pain.
The compounds of the invention may also possess anti-inflammatory, anti-pyretic and anti-diarrhoeal properties and be effective in other conditions in which prostaglandin E2 (PGE2) wholly or in part plays a pathophysiological role.
According to the invention there is provided a compound of the formula I; 
wherein:
A is an optionally substituted:
phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl, thiadiazolyl having at least two adjacent ring carbon atoms or a bicyclic ring system of the formula: 
wherein E is nitrogen or CH, F is nitrogen or CH, G is sulphur or oxygen and H is nitrogen or CH;
provided that the xe2x80x94Zxe2x80x94Bxe2x80x94R1 and xe2x80x94Xxe2x80x94D linking groups are positioned in a 1,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the xe2x80x94Xxe2x80x94 linking group (and therefore in the 3-position relative to the xe2x80x94Zxe2x80x94 linking group) is not substituted;
B is an optionally substituted:
phenyl, pyridyl, thiazolyl, oxazolyl, thienyl, thiadiazolyl, isoxazole, pyrazole, furyl, pyrrolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidyl, pyridone, pyrimidone, pyrazinone or pyridazinone;
D is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or phenyl;
R1 is positioned on ring B in a 1,3 or 1,4 relationship with the xe2x80x94Zxe2x80x94 linking group in 6-membered rings and in a 1,3-relationship with the xe2x80x94Zxe2x80x94 linking group in 5-membered rings and is carboxy, carboxyC1-3 alkyl, tetrazolyl, tetrazolylC1-3alkyl, tetronic acid, hydroxamic acid, sulphonic acid, or R1 is of the formula xe2x80x94SO2NHRe wherein Re is hydrogen or C1-6alkyl; or R1 is of the formula (IIA), (IIB) or (IIC): 
xe2x80x83wherein Xxe2x80x3 is CH or nitrogen, Y is oxygen or sulphur Yxe2x80x2 is oxygen or NH, and Z is CH2, NH or oxygen provided that there is no more than one ring oxygen and there are at least two ring heteroatoms; or R1 is of the formula xe2x80x94CONRaRa1 or xe2x80x94C1-3alkylCONRaRa1 wherein Ra is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-3alkyl, C5-7cycloalkenyl or C5-7cycloalkenylC1-3alkyl and Ra1 is hydrogen, hydroxy or optionally substituted: C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, C3-7cycloalkylC2-6alkenyl, C3-7cycloalkylC2-6alkynyl, C5-7cycloalkenyl, C3-7cycloalkenylC1-6alkyl, C5-7cycloalkenylC2-6alkenyl, C5-7cycloalkenylC2-6alkynyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylC1-6alkyl, 5- or 6-membered saturated or partially saturated heterocyclyl or 5- or 6-membered saturated or partially saturated heterocyclylC1-6alkyl; or wherein Ra and Ra1 together with the amide nitrogen to which they are attached (NRaRa1) form an amino acid residue or ester thereof; or R1 is of the formula xe2x80x94CONHSO2Rb or xe2x80x94C1-3alkylCONHSO2Rb wherein Rb is optionally substituted: C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, C3-7cycloalkylC2-6alkenyl, C3-7cycloalkylC2-6alkynyl, C5-7cycloalkenyl, C3-7cycloalkenylC1-6alkyl, C5-7cycloalkenylC2-6alkenyl, C5-7cycloalkenylC2-6alkynyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroylarC16alkyl, phenyl, phenylC1-6alkyl, 5- or 6-membered saturated or partially saturated heterocyclyl or 5- or 6-membered saturated or partially saturated heterocyclylC1-6alkyl or R1 is of the formula xe2x80x94CONRaN(Rc)Rd or xe2x80x94C1-3alkylCONRaN(Rc)Rd wherein Ra is as hereinabove defined, Rc is hydrogen or C1-6alkyl and Rd is hydrogen, hydroxy or optionally substituted: C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, C3-7cycloalkylC2-6alkenyl, C3-7cycloalkylC2-6alkynyl, C5-7cycloalkenyl, C5-7cycloalkenylC1-6alkyl, C5-7cycloalkenylC2-6alkenyl, C5-7cycloalkenylC2-6alkynyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylC1-6alkyl, 5- or 6-membered saturated or partially saturated heterocyclyl, 5- or 6-membered saturated or partially saturated heterocyclylC1-6alkyl, or Rc and Rd, together with the nitrogen atom to which they are attached, form a 4 to 8-membered saturated or partially saturated heterocyclic ring or form an amino acid residue or ester thereof;
X is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NH(R4)CH2 wherein the left hand atom is attached to A and the right hand atom is attached to D;
Z is of the formula xe2x80x94CH(R3)CH(R3)N(R2)xe2x80x94, xe2x80x94N(R2)CH(R3)xe2x80x94, xe2x80x94CH(R3)P1xe2x80x94, xe2x80x94(CH(R3))mxe2x80x94 or xe2x80x94CH(R3)N(R2)xe2x80x94
wherein
R2 is hydrogen, C1-6alkyl (optionally substituted by hydroxy, cyano, nitro, amino, halo, C1-4alkanoyl, C1-14alkoxy or trifluoromethyl) C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkylC1-3alkyl, C3-6cycloalkylC2-3alkenyl, C5-6cycloalkenyl, C5-6cycloalkenylC1-3alkyl, C5-6cycloalkenylC2-3alkenyl, phenyl, phenylC1-3alkyl or 5- or 6-membered heteroarylC1-3alkyl;
R3 is hydrogen or C1-4alkyl;
P1 is oxygen or sulphur, m is 2 or 3 and R4 is hydrogen or C1-4alkyl and wherein the left hand atom is attached to A and the right hand atom is attached to B; provided that when Z is xe2x80x94CH(R3)N(R2)xe2x80x94 or xe2x80x94(CH(R3))mxe2x80x94, X is not xe2x80x94OCH2xe2x80x94; and N-oxides of xe2x80x94NR2 where chemically possible;
and S-oxides of sulphur containing rings where chemically possible;
and pharmaceutically acceptable salts and in vivo hydrolysable esters and amides thereof, excluding 4-[4-acetyl-2-benzyl-3-hydroxyphenoxymethyl]-3-methoxybenzoic acid.
A 5- or 6-membered heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen and sulphur.
A 5- or 6-membered saturated or partially saturated heterocyclic (heterocyclyl) ring is a ring system having 5 or 6 ring atoms wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulphur.
Particular 5- or 6-membered monocyclic heteroaryl rings include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl and oxazolyl.
Particular 5- or 6-membered saturated or partially saturated heterocyclic ring ring systems include pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.
The linking group xe2x80x94CH(R3)N(R2)CH(R3)xe2x80x94 includes xe2x80x94CH2N(R2)CH(Me)xe2x80x94, xe2x80x94CH2N(R2)CH2xe2x80x94and xe2x80x94CH(Me)N(R2)CH2xe2x80x94.
The linking group xe2x80x94CH(R3)CH(R3)N(R2)xe2x80x94 includes xe2x80x94CH2CH(Me)N(R2)xe2x80x94, xe2x80x94CH(Me)CH2N(R2)xe2x80x94 and xe2x80x94CH2CH2N(R2)xe2x80x94.
The linking group xe2x80x94(CH(R3))mxe2x80x94 includes xe2x80x94(CH(Me))2xe2x80x94, xe2x80x94CH2CH(Me)xe2x80x94, xe2x80x94CH(Me)CH2xe2x80x94 and xe2x80x94(CH2)3xe2x80x94.
Particular substituents for ring carbon atoms in A and D include halo, trifluoromethyl, nitro, hydroxy, amino, C1-4alkylamino, diC1-4alkylamino, cyano, C1-6alkoxy, xe2x80x94S(O)pC1-6alkyl (p is 0, 1 or 2), C1-6alkyl (optionally substituted by hydroxy, amino, halo, nitro or cyano), xe2x80x94S(O)pCF3 (p=0, 1 or 2), carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C2-6alkenyl, C2-6alkynyl, C2-4alkenylamino, Nxe2x80x94C2-4alkenyl-Nxe2x80x94C1-4alkylamino, di-C2-4alkenylamino, S(O)pC2-6alkenyl, C2-4alkenylcarbamoyl, Nxe2x80x94C2-4alkenyl-N-alkylamino, di-C2-4alkenylcarbamoyl, C3-7cycloalkyl, C3-7cycloalkylC1-3alkyl, C3-7cycloalkylC2-3alkenyl, C5-7cycloalkenyl, C5-7cycloalkenylC1-3alkyl, C5-7cycloalkenylC2-3alkenyl, C5-7cycloalkenylC2-3alkynyl, C1-4alkoxycarbonylamino, C1-4alkanoylamino, C1-4alkanoyl(Nxe2x80x94C1-4alkyl)amino, C1-4alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C1-4alkylaminosulphonyl, di(C1-4alkyl)aminosulphonyl, C1-4alkoxycarbonyl, C1-4alkanoyloxy, C1-6alkanoyl, formylC1-4alkyl, trifluoroC1-3alkylsulphonyl, hydroxyiminoC1-6alkyl, C1-4alkoxyiminoC1-6alkyl C1-6alkylcarbamoylamino, oxazolyl, pyridyl, thiazolyl, pyrimidyl, pyrazinyl and pyridazinyl.
Where a ring nitrogen atom in A can be substituted without becoming quaternised, it is unsubstituted or substituted by C1-4alkyl.
Particular substituents for ring carbon atoms in B include halo, amino, C1-4alkylamino, di(C1-4alkyl)amino, trifluoromethyl, nitro, hydroxy, C1-6alkoxy, C1-6alkyl, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano, xe2x80x94S(O)pC1-6alkyl (p is 0, 1 or 2), carbamoyl, C1-4alkylcarbamoyl and di(C1-4alkyl)carbamoyl.
Where a ring nitrogen atom in B can be substituted without becoming quaternised, it is unsubstituted or substituted by C1-4alkyl.
Particular substituents for optionally substituted groups in Ra1 Rb and Rd include those mentioned above for ring A.
Particular substituents for carbon atoms in optionally substituted groups in Ra1 include halo, hydroxy, C1-4alkyl, nitro, cyano, amino, carboxy, trifluoromethyl, C1-4alkoxy, C3-7cycloalkyl, C5-7cycloalkenyl, C3-7cycloalkylC1-3alkyl, C5-7cycloalkenylC1-3alkyl, C3-7cycloalkylC2-3alkenyl, C5-7cycloalkenylC2-3alkenyl and C1-4alkoxycarbonyl. Particular substituents for optionally substituted groups in Rb include halo, trifluoromethyl, nitro, C1-4alkyl, hydroxy, amino, cyano, amino, C1-6alkoxy, S(O)pC1-6alkyl (p is 0, 1 or 2), carbamoyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C5-7cycloalkenyl, C3-7cycloalkylC1-3alkyl, C5-7cycloalkenylC1-3alkyl, C3-7cycloalkylC2-3alkenyl, C5-7cycloalkenylC2-3alkenyl, C1-4alkoxycarbonylamino, C1-4alkanoylamino, C1-4alkanoyl(Nxe2x80x94C1-4alkyl)amino, C1-4alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C1-4alkylaminosulphonyl, di(C1-4alkyl)aminosulphonyl, C1-4alkoxycarbonyl, C1-4alkanoyloxy, C1-6alkanoyl, formylC1-4alkyl, hydroxyiminoC1-6alkyl, C1-4alkoxyiminoC1-6alkyl and C1-6alkylcarbamoylamino.
The term alkyl when used herein includes straight chain and branched chain substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl and functional groups on alkyl chains may be anywhere on the chain, for example hydroxyiminoC1-6alkyl includes 1-(hydroxyimino)propyl and 2-(hydroxyimino)propyl.
Examples of C1-6alkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; examples of carboxyC1-3alkyl are carboxymethyl, 2-carboxyethyl, 1-carboxyethyl and 3-carboxypropyl; examples of C1-6alkoxycarbonylC1-3alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples of tetrazolylC1-3alkyl are tetrazolylmethyl and 2-tetrazolylethyl; examples of C1-4alkoxy are methoxy, ethoxy, propoxy and isopropoxy; examples of C2-6alkenyl are vinyl and allyl; examples of C2-6alkynyl are ethynyl and propynyl; examples of C1-4alkanoyl are formyl, acetyl, propionyl and butyryl; examples of halo are fluoro, chloro, bromo and iodo; examples of C1-4alkylamino are methylamino, ethylamino, propylamino and isopropylamino; examples of di(C1-4alkyl)amino are dimethylamino, diethylamino and ethylmethylamino; examples of xe2x80x94S(O)pC1-4alkyl are methylthio, methylsulphinyl and methylsulphonyl; examples of C1-4alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examples of di(C1-14alkyl)carbamoyl are dimethylcarbamoyl, diethylcarbamoyl and ethylmethylcarbamoyl; examples of C1-6alkyl are methyl, ethyl, propyl and isopropyl; examples of C3-7cycloalkyl are cyclopropyl, cyclobutyl and cyclohexyl; examples of C3-7cycloalkylC1-3alkyl are cyclopropylmethyl and cyclohexylmethyl; examples of C3-7cycloalkylC2-3alkenyl are cyclopropylethenyl and cyclopentylpropenyl; examples of C3-7cycloalkylC2-3alkynyl are cyclopropylethynyl and cyclopentylethynyl; examples of C5-7alkenyl are cyclopentenyl and cyclohexenyl; examples of C5-7cycloalkenylC1-3alkyl are cyclopentenylmethyl and cyclohexenylmethyl; examples of C5-7cycloalkenylC2-3alkenyl are cyclohexenylethenyl and cycloheptenylethenyl; examples of C5-7cycloalkenylC2-3alkynyl are cyclopentenylethynyl and cyclohexenylethynyl; examples of C1-4alkoxycarbonylamino are methoxycarbonylamino and ethoxycarbonylamino; examples of C1-4alkanoylamino are acetamido and propionamido; examples of C1-4alkanoyl(Nxe2x80x94C1-4alkyl)amino are N-methylacetamido and N-methylpropionamido; examples of C1-4alkanesulphonamido are methanesulphonamido and ethanesulphonamido; examples of C1-4alkylaminosulphonyl are methylaminosulphonyl and ethylaminosulphonyl; examples of di(C1-4alkyl)aminosulphonyl are dimethylaminosulphonyl, diethylaminosulphonyl and ethylmethylaminosulphonyl; examples of C1-4alkanoyloxy are acetyloxy and propionyloxy; examples of formylC1-4alkyl are formylmethyl and 2-formylethyl; examples of hydroxyiminoC1-6alkyl are hydroxyiminomethyl and 2-(hydroxyimino)ethyl; and examples of C1-4alkoxyiminoC1-6alkyl are methoxyiminomethyl, ethoxyiminomethyl and 2-(methoxyimino)ethyl.
Suitable ring systems of the formula (IIA), (IIB) or (IIC) include 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 3-oxo-2,3-dihydro-1,2,4-oxadiazol-5-yl, 3-thioxo-2,3-dihydro-1,2,4-oxadiazol-5-yl, 5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl, 5-oxo-4,5-dihydro-1,2,4-triazol-3-yl, 3-oxo-2,3-dihydroisoxazol-5-yl, 5-oxo-1,5-dihydroisoxazol-3-yl and 5-oxo-2,3-dihydropyrazol-3-yl.
Amino acid residues formed from Ra and Ra1 together with the amide nitrogen to which they are attached and esters thereof include for example radicals of the formula xe2x80x94NHxe2x80x94CH(Rc)xe2x80x94COORd wherein Rc is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, phenylC1-3alkyl, 5- or 6-membered heteroaryl or 5- or 6-membered heteroarylC1-3alkyl and Rd is hydrogen or C1-6alkyl, wherein alkyl, alkenyl, alkynyl, phenyl and heteroaryl groups are optionally substituted. Examples of substituents include those mentioned above for ring A. In particular hydroxy.
When an alkenyl or alkynyl group is directly linked to the nitrogen of a primary or secondary amine it will be appreciated that the double or triple bond may not be in the 1-position. Similarly alkyl groups which are substituted by halo, hydroxy or an amine may not be substituted by these substituents in the 1-position when the alkyl group is directly linked to the nitrogen of a primary or secondary amine.
Preferably A is an optionally substituted:
phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl or thiadiazolyl having at least two adjacent ring carbon atoms;
More preferably A is optionally substituted:
phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl or pyrimidyl.
Most preferably A is optionally substituted: phenyl or thienyl.
In particular A is optionally substituted phenyl.
Preferably B is optionally substituted:
pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl, thiadiazolyl, imidazolyl, pyrazinyl, pyrimidyl, or oxazolyl.
More preferably B is optionally substituted:
pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl or oxazolyl.
Yet more preferably B is optionally substituted:
pyridyl, phenyl, thienyl, pyridazinyl or thiazolyl.
Yet more preferably B is optionally substituted:
phenyl, pyridyl or pyridazinyl.
Most preferably B is pyridazinyl.
Preferably D is optionally substituted: pyridyl, thienyl, thiazolyl, furyl or phenyl.
More preferably D is optionally substituted: thienyl, furyl or phenyl.
Most preferably D is optionally substituted phenyl.
Preferred optional substituents for ring carbon atoms in A, are halo, nitro, trifluoromethyl, cyano, amino, C1-6alkoxy, carbamoyl, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-3alkyl, C3-7cycloalkylC2-3alkenyl, C5-7cycloalkenyl, C5-7cycloalkenylC1-3alkyl, C5-7cycloalkenylC2-3alkenyl, C1-4alkylcarbamoyl, di(C1-4alkyl)carbamoyl, C1-4alkanoylamino, S(O)pC1-6alkyl, C1-4alkanesulphonamido, benzenesulphonamido, C1-6alkanoyl, C1-4alkoxyiminoC1-4alkyl and hydroxyiminoC1-4alkyl.
Most preferred optional substituents for ring carbon atoms in A are chloro, bromo and methanesulphonyl.
In particular A is substituted on a ring carbon atom by bromo.
Preferably, when A is a 6-membered ring, A is unsubstituted or substituted in the 4-position relative to the xe2x80x94Xxe2x80x94 linking group. Preferred optional substituents for ring carbon atoms of B are halo, amino, diC1-4alkylamino, C1-4alkylamino, trifluoromethyl, nitro, hydroxy, methyl, C1-4alkyl, C1-4alkoxy and cyano.
More preferred optional substituents for ring carbon atoms of B are fluoro, chloro, bromo, trifluoromethyl, hydroxy, methyl, methoxy and cyano.
Preferably D is optionally substituted by 1 or 2 substituents selected from halo, trifluoromethyl, nitro, hydroxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, cyano, C1-6alkoxy, xe2x80x94S(O)pC1-4alkyl (p is 0, 1 or 2), C1-4alkanoyl, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-3alkyl, C3-7cycloalkylC2-3alkenyl, C5-7cycloalkenyl, C5-7cycloalkenylC1-3alkyl, C5-7cycloalkenylC2-3alkenyl, wherein C3-7cycloalkyl, C5-7cycloalkenyl, C1-6alkyl and C1-6alkyloxy are optionally substituted by trifluoromethyl, hydroxy, halo, nitro, cyano or amino.
Most preferred optional substituents for D include halo, nitro, hydroxy, cyano, C1-6alkyl, amino, C1-6alkoxy or carbamoyl. Most preferably D is unsubstituted.
Preferably A is unsubstituted or substituted by one substituent.
Preferably B is unsubstituted or substituted by one substituent.
Preferably R1 is carboxy, carbamoyl, tetrazolyl or of the formula xe2x80x94CONRaRa1 or xe2x80x94CONHSO2Rb.
Preferably, Ra1 is hydrogen, hydroxy or optionally substituted: C1-6alkyl, C2-6alkenyl, C2-6alkynyl, cyclopropylC1-4alkyl, cyclobutylC1-4alkyl, cyclopentylC1-4alkyl, cyclohexylC1-4alkyl, pyridylC1-4alkyl, pyrimidylC1-4alkyl, pyrazinylC1-4alkyl, furylC1-4alkyl, pyridazinylC1-4alkyl, tetrazolylC1-4alkyl, pyrrolidinylC1-4alkyl, morpholinylC1-4alkyl, imidazoliumC1-4alkyl, N-methylimidazoliumC1-4alkyl, pyridiniumC1-4alkyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, N-methylpyrimidinium, N-methylimidazolyl, pyridinium, pyrimidinium, tetrazolyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclopentenylC1-4alkyl, cyclohexenylC1-4alkyl or cycloheptenylC1-4alkyl.
More preferably Ra1 is hydrogen, C1-6alkyl (optionally substituted by halo, hydroxy, nitro, cyano, amino, carboxy, C1-4alkoxycarbonyl), pyridylC1-4alkyl, pyrimidylC1-4alkyl, pyrazinylC1-4alkyl, furylC1-4alkyl, pyridazinylC1-4alkyl, tetrazolylC1-4alkyl, or C2-6alkenyl.
Most preferably Ra1 is C1-4alkyl (optionally substituted by one or two substituents selected from hydroxy, carboxy and C1-4alkoxycarbonyl), pyridylC1-4alkyl and furylC1-4alkyl.
Preferably xe2x80x94C1-3alkylCONRaRa1 is xe2x80x94CH2CONRaRa1.
Preferably xe2x80x94C1-3alkylCONHSO2Rb is xe2x80x94CH2CONHSO2Rb.
Preferably xe2x80x94C1-3alkylCONRaNRcRd is xe2x80x94CH2CONRaNRcRd.
Preferably Rb is optionally substituted: C1-6alkyl,
C3-7cycloalkyl, C3-7cycloalkylC1-3alkyl, C3-7cycloalkylC2-3alkenyl, C5-7cycloalkenyl, C5-7cycloalkenylC1-3alkyl, C5-7cycloalkenylC2-3alkenyl, 5- or 6-membered heteroarylC1-3alkyl, 5- or 6-membered saturated or partially saturated heterocyclylC1-3alkyl, phenylC1-3alkyl, phenyl, 5- or 6-membered heteroaryl or 5- or 6-membered saturated or partially saturated heterocyclyl.
More preferably Rb is C1-4alkyl (optionally substituted by hydroxy, nitro, cyano, amino, C1-4alkylamino, di-C1-4alkylamino, C1-4alkanoylamino, C1-4alkyl-Nxe2x80x94C1-4alkanoylamino, carbamoyl, C1-4alkylcarbamoyl, di-C1-4alkanoylcarbamoyl, halo, C1-4alkoxy) or optionally substituted phenylC1-3alkyl, pyridylC1-3alkyl, phenyl, thienyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl or 1,1-dioxidotetrahydrothienyl.
Most preferably Rb is C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, phenyl (optionally substituted by halo, cyano, nitro, carbamoyl, C1-4alkylcarbamoyl, di-C1-4alkylcarbamoyl, hydroxy, amino, C1-4alkanoylamino, Nxe2x80x94C1-4alkanoyl-Nxe2x80x94C1-4alkylamino, C1-4alkylamino or di-(C1-4alkyl)amino), benzyl (optionally substituted by halo, cyano, nitro, carbamoyl, C1-4alkylcarbamoyl, di-C1-4alkylcarbamoyl, hydroxy, amino, C1-4alkanoylamino, Nxe2x80x94C1-4alkanoyl-Nxe2x80x94C1-4alkylamino, C1-4alkylamino or di-(C1-4alkyl)amino), thiadiazolyl (optionally substituted by C1-4alkanoylamino, amino, C1-4alkylamino or di-C1-4alkylamino), thienyl (optionally substitued by halo or pyridyl), isoxazolyl (optionally substituted by C1-4alkyl or halo), pyrazolyl (optionally substituted by C1-4alkyl or halo) or 1,1-dioxidotetrahydro-2-thienyl.
Preferably Rc is hydrogen and Rd is 5- or 6-membered heteroaryl or Rc and Rd, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated or partially saturated heterocyclic ring.
More preferably Rc is hydrogen and Rd is pyridyl or Rc and Rd, together with the nitrogen atom to which they are attached, form morpholino.
Preferably R1 is carboxy, carbamoyl, tetrazolyl or of the formula xe2x80x94CONRaRa1 or xe2x80x94CONHSO2Rb.
Most preferably R1 is carboxy.
More preferably R2 is hydrogen, methyl, ethyl, cyclopropylmethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyanomethyl, allyl or 2-propynyl.
Most preferably R2 is hydrogen, ethyl, allyl or 2-propynyl.
In particular R2 is hydrogen or ethyl.
Preferably R3 is hydrogen, methyl or ethyl.
Most preferably R3 is hydrogen.
R3, is R3 with the proviso that R3a is not hydrogen.
Most preferably R4 is hydrogen.
In one aspect A is optionally substituted: naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl, thiadiazolyl having at least two adjacent ring carbon atoms or a bicyclic ring system of the formula: 
wherein E is nitrogen or CH, F is nitrogen or CH, G is sulphur or oxygen and H is nitrogen or CH.
In another aspect A is optionally substituted phenyl.
Preferably m is 2.
In one aspect P1 is oxygen.
In another aspect P1 is sulphur.
Preferably R4 is hydrogen, methyl or ethyl.
Most preferably R4 is hydrogen.
When xe2x80x94Zxe2x80x94 is xe2x80x94CH(R3)P1xe2x80x94, xe2x80x94CH(R3)CH(R3)N(R2)xe2x80x94 or xe2x80x94N(R2)CH(R3)xe2x80x94,
xe2x80x94Xxe2x80x94 is preferably xe2x80x94OCH2xe2x80x94.
When xe2x80x94Zxe2x80x94 is xe2x80x94[CH(R3)]mxe2x80x94, xe2x80x94Xxe2x80x94 is preferably xe2x80x94CH2CH2xe2x80x94 or xe2x80x94NHCH2xe2x80x94.
When xe2x80x94Zxe2x80x94 is xe2x80x94CH(R3)N(R2)xe2x80x94, xe2x80x94Xxe2x80x94 is preferably xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94NHCH2xe2x80x94.
A preferred class of compounds is that of the formula (II): 
wherein
Z, X, R1 and R2 are as hereinabove defined, n is 0 or 1, R5 is hydrogen or as hereinabove defined for substituents for ring carbon atoms in D, R6 is hydrogen or as hereinabove defined for substituents for ring carbon atoms in A and B is phenyl, thienyl, pyridazinyl, pyridyl, or thiazolyl.
It is to be understood that, insofar as certain of the compounds of formula (I) defined above may exist in optically active or racemic forms, by virtue of the compounds of the formula (I) containing an asymmetric carbon atom, the invention includes in its definition of active ingredient any such optically active or racemic form which possesses pain relieving properties. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, pain relieving properties may be evaluated using the standard laboratory techniques referred to hereinafter.
An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid, for example, a pharmaceutically acceptable ester formed with a (1-6C)alcohol such as methanol, ethanol, ethylene glycol, propanol or butanol, or with a phenol or benzyl alcohol such as phenol or benzyl alcohol or a substituted phenol or benzyl alcohol wherein the substituent is, for example, a halo (such as fluoro or chloro), (1-4C)alkyl (such as methyl) or (1-4C)alkoxy (such as ethoxy) group. The term also includes xcex1-acyloxyalkyl esters and related compounds which breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl esters include acetoxymethoxycarbonyl and 2,2-dimethylpropionyloxymethoxycarbonyl. An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent alcohol. The term includes inorganic esters such as phosphate esters and xcex1-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
A suitable value for an in vivo hydrolysable amide of a compound of the formula I containing a carboxy group is, for example, a N-(1-6C)alkyl or N,N-di-(1-6C)alkyl amide such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.
A suitable pharmaceutically-acceptable salt of a compound of the formula (I) is, for example, an acid-addition salt of a compound of the formula (I) which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of the formula (I) which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
In a further aspect the invention provides a process for preparing compounds of the formula (I) or pharmaceutically acceptable salts or in vivo hydrolysable amides or ester thereof, which comprises deprotecting a compound of the formula (III): 
wherein R7 is R1 or protected R1, xe2x80x94Z1xe2x80x94 is xe2x80x94Zxe2x80x94 or protected xe2x80x94Zxe2x80x94, R2, R3, Z, X, A, B and D are as hereinabove defined, and any optional substituents are optionally protected and at least one protecting group is present;
and thereafter if necessary;
i) forming a pharmaceutically acceptable salt;
ii) forming an in vivo hydrolysable ester or amide;
iii) converting one optional substituent into another optional substituent.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
A suitable protecting group for a hydroxy group is, for example, an arylmethyl group (especially benzyl), a tri-(1-4C)alkylsilyl group (especially trimethylsilyl or tert-butyldimethylsilyl), an aryldi-(1-4C)alkylsilyl group (especially dimethylphenylsilyl), a diaryl-(1-4C)alkylsilyl group (especially tert-butyldiphenylsilyl), a (1-4C)alkyl group (especially methyl), a (2-4C)alkenyl group (especially allyl), a (1-4C)alkoxymethyl group (especially allyl), a (1-4C)alkoxymethyl group (especially methoxymethyl) or a tetrahydropyranyl group (especially tetrahydropyran-2-yl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal. Alternatively a trialkylsilyl or an aryldialkylsilyl group such as a tert-butyldimethylsilyl or a dimethylphenylsilyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric, phosphoric or trifluoroacetic acid, or with an alkali metal or ammonium fluoride such as sodium fluoride or, preferably, tetrabutylammonium fluoride. Alternatively an alkyl group may be removed, for example, by treatment with an alkali metal (1-4C)alkylsulphide such as sodium thioethoxide or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide or, for example, by treatment with a boron or aluminium trihalide such as boron tribromide. Alternatively a (1-4C)alkoxymethyl group or tetrahydropyranyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric or trifluoroacetic acid.
Alternatively a suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl) or an aroyl group (especially benzoyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
A suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), a (1-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl). The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl, alkoxycarbonyl or aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a (1-4C)alkyl group (especially methyl or ethyl) which may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide; or, for example, a tert-butyl group which may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid.
In another aspect the compounds of the formula (I) or (III) may be prepared by:
a) when xe2x80x94Z1xe2x80x94 is xe2x80x94CH(R3)NHCH(R3)xe2x80x94, xe2x80x94CH(R3)CH(R3)NHxe2x80x94, xe2x80x94CH(R3)NHxe2x80x94 or xe2x80x94NHCH(R3)xe2x80x94 reducing a compound of the formula (IVa) or (IVb): 
b) when xe2x80x94Z1xe2x80x94 is xe2x80x94CH(R3)N(R8)CHR3), xe2x80x94CH(R3)CH(R3)N(R8)xe2x80x94 or xe2x80x94CH(R3)N(R9)xe2x80x94 and B is an activated heterocycle and R8 is hydrogen or C1-6alkyl, reacting a compound of the formula (V) with a compound of the formula (VI): 
c) converting R10 to R7 in a compound of the formula (VII): 
d) when xe2x80x94Z1xe2x80x94 is xe2x80x94CH(R3)N(R8)xe2x80x94, xe2x80x94N(R8)CH(R3)xe2x80x94 or xe2x80x94CH(R3)CH(R3)N(R8)xe2x80x94 and R8 is other than hydrogen, reacting a compound of the formula R8X2 with a compound of the formula (VIII): 
e) when xe2x80x94Z1xe2x80x94 is xe2x80x94CH(R3)N(R8)CH(R3)xe2x80x94, xe2x80x94CH(R3)CH(R3)N(R8)xe2x80x94 or xe2x80x94CH(R3)N(R8)xe2x80x94, reacting a compound of the formula (IX) with a compound of the formula (X): 
f) when X is xe2x80x94CH2CH2xe2x80x94, reducing a compound of the formula (XIA) or (XIB): 
g) when X is xe2x80x94CH2xe2x80x94, hydrogenating a compound of the formula (XII): 
h) when X is xe2x80x94CH2xe2x80x94, reacting a compound of the formula (XIII) with a compound of the formula X3-D 
i) when X is xe2x80x94Oxe2x80x94, reacting a compound of the formula (XIV) with a compound of the formula X5-D: 
j) when X is xe2x80x94NHCH2xe2x80x94, reacting a compound the formula (XV) with a compound of the formula X7CH2D or D-CHO: 
k) when X is xe2x80x94OCH2xe2x80x94, reacting a compound of the formula L1-CH2D with a compound of the formula (XVI): 
l) when X is xe2x80x94N(R4)CH2xe2x80x94, reacting a compound of the formula (XVII) with a compound of the formula R4X8: 
m) when xe2x80x94Z1xe2x80x94 is of the formula xe2x80x94CH(R3)CH2N(R8)xe2x80x94, reducing a compound of the formula (XVIII) 
n) when xe2x80x94Z1xe2x80x94 is of the formula xe2x80x94[CH(R3)]mxe2x80x94, by reducing a compound of the formula (XIXa) or (XIXb): 
o) when xe2x80x94Z1xe2x80x94 is of the formula xe2x80x94[CH(R3)]mxe2x80x94, and m is 3, by reducing a compound of the formula (XX): 
p) when xe2x80x94Z1xe2x80x94 is of the formula xe2x80x94[CH(R3)]mxe2x80x94, and B is an activated heterocycle by reacting a compound of the formula (XXI) with a compound of the formula (XXII): 
q) when xe2x80x94Z1xe2x80x94 is of the formula xe2x80x94CH(R3)P1xe2x80x94, reacting a compound of the formula HP1xe2x80x94Bxe2x80x94R7 with a compound of the formula (XXIII): 
r) when xe2x80x94Z1xe2x80x94 is of the formula xe2x80x94CH(R3)P1xe2x80x94, reacting a compound of the formula X14xe2x80x94Bxe2x80x94R7 with a compound of the formula (XXIV): 
s) when xe2x80x94Z1xe2x80x94 is of the formula xe2x80x94N(R8)CH(R3)xe2x80x94, reacting a compound of the formula (XXV) with a compound of the formula (VI): 
wherein R3, R7, Z1, A, B, D and X as hereinabove defined, R8 is R2 or protected R2, X1 is a leaving group, R10 is a precursor of R7, X2 is a leaving group, R11 is a removable activating group, R12 is a leaving group, either X3 is a leaving group and X4 is ZnX3 or X4 is a leaving group and X3 is ZnX4, either X5 is a leaving group and X6 is hydroxy or X6 is hydroxy and X5 is a leaving group, L1, X7 X8, X9, X13 and X14 are leaving groups and p and q are independently 0 or 1 provided that p and q are not both 1; and thereafter if necessary:
i) removing any protecting groups;
ii) forming a pharmaceutically acceptable salt;
iii) forming an in vivo hydrolysable ester or amide;
iv) converting an optional substituent into another optional substituent.
Particular values for leaving groups include halogen, for example, chloro, bromo and iodo, sulphonates, for example tosylate, p-bromobenzenesulphonate, p-nitrobenzenesulphonate, fluorosulphonate, methanesulphonate and triflate or phosphoric esters such as a diarylphosphoric ester.
Compounds of the formula (IVa) and (IVb) can be reduced using agents such as odium borohydride or sodium cyanoborohydride. The compounds of the formula (IVa) may be prepared by reacting a compound of the formula (X) with a compound of the formula (XVa1) 
wherein A, X, D and p are as hereinabove defined.
The reaction between compounds of the formulae (X) and (IVa1) may be carried out under standard conditions known in the art for the formation an imine (Schiffs base), which can be reduced in situ. For example imine formation and reduction in situ may be carried out in an inert solvent such as toluene or tetrahydrofuran, in the presence of a reducing agent such as sodium cyanoborohydride (NaCNBH3) under acidic conditions (Synthesis 135, 1975; Org. Prep. Proceed. Int. 11, 201, 1979). When p is 1 and R3 is hydrogen, compounds of the formula (IVa1) may be prepared by reducing a compound of the formula (XVIIIA)xe2x80x94see scheme 1.
The compounds of the formula (IVb) may be formed by reacting a compound of the formula R7xe2x80x94Bxe2x80x94C(xe2x95x90O)R3 with a compound of the formula (IVb1) 
and reducing the product in situ, wherein A, D and X are as hereinabove defined.
The reaction between compounds of the formulae R7xe2x80x94Bxe2x80x94C(xe2x95x90O)xe2x80x94R3 and (IVb1) is normally carried out as reductive alkylation. In this reaction the compound of the formula (IVb1) is reduced to the related amine, which reacts with the compound of the formula R7xe2x80x94Bxe2x80x94C(xe2x95x90O)xe2x80x94R3 to give a compound of the formula (IVb) which is immediately reduced to a compound of the formula (I) or (III) in situ. Alternatively one or more steps could be performed separately. Palladium-on-carbon is commonly used as the reducing agent in this reaction.
Compounds of the formulae (V) and (VI) may be reacted together under standard conditions for example, in an aprotic solvent such as DMF in the presence of a weak base, in a temperature range of ambient to 180xc2x0 C. Suitable bases include sodium hydrogen carbonate and amide bases such as Hunig""s base, N-ethyl-N,N-diisopropylamine, tributylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Suitable values for X1 include, halo, tosylate, mesylate and triflate. In particular X1 is chloro or bromo.
In general this process is best used when ring B is an electron poor heterocycle such as pyridine, pyrimidine, pyridazine or pyrazine.
Compounds of the formula (V) wherein p is 1 are conveniently prepared from compounds of the formula (VA) as shown in scheme 1. Compounds of the formula (VB) in which X15 is a leaving group, such as bromo, are reacted with a cyanide salt such as potassium cyanide in a solvent such as DMF, in a temperature range of 20-140xc2x0 C. to give a compound of the formula (VC). 18 Crown 6 may be added as a catalyst. The compound of the formula (VC) may be reduced by catalytic hydrogenation with, for example, palladium on carbon, borane.THF, borane.DMS complexes, lithium aluminium hydride or lithium borohydide/trimethylsilyl chloride to give a compound of the formula (VA). Alternatively, a compound of the formula (VD) may be prepared by reacting the compound of the formula (VE) with CH3NO2 in the Henry reaction. The reaction is performed in the presence of an amine base such as triethylamine, in THF or CH3NO2 as solvent, in a temperature range of 0-20xc2x0 C. The compound of the formula (VD) may then be reduced with a strong reducing reagent such as lithium aluminium hydride or by hydrogenation with palladium-on-carbon as the catalyst, to give a compound of the formula (VA). When R8 is other than hydrogen, compounds of the formula (V) may be prepared by alkylating the compound of the formula (VA) using a similar reaction to that described in process d).
Particular values for R10 include cyano, carbamoyl, alkoxycarbonyl, carboxy and activated carboxy groups such as acid chlorides and activated esters.
The cyano group may be converted into a tetrazole ring by reacting it with, for example, ammonium or tin azide in an aprotic solvent such as DMF, in a temperature range of 100xc2x0 C. to 130xc2x0 C. For further information on tetrazole synthesis see S. J. Wittenberger and B. J. Donner JOC, 1993, 58, 4139-4141; BE Huff et al, Tet. Lett, 1993, 50, 8011-8014; and J. V. Duncia et al, JOC 1991, 56, 2395-2400.
Alkoxycarbonyl may be converted into a carboxy group by acid or base hydrolysis. For example, base hydrolysis may be carried out in an organic solvent such as methanol or THF in a temperature range of ambient to 100xc2x0 C., in the presence of sodium hydroxide or potassium hydroxide.
Acid hydrolysis may, for example, be carried out in neat formic acid or neat trifluoroacetic acid optionally in an organic solvent such as dichloromethane.
An alkoxycarbonyl or an activated carboxy group, such as an acid chloride or activated ester, or an acyl group such as an alkanoyl group may be converted to an amide group by reacting it with the appropriate amine in an inert solvent such as DMF or dichloromethane, in a temperature range of 0xc2x0 C. to 150xc2x0 C., preferably around ambient temperature, in the presence of a base such as triethylamine.
The compounds of the formulae (VIII) and R8X2 may be reacted together in an aprotic solvent such as DMF in the presence of a base such as sodium carbonate or sodium hydride. Suitable values for X2 are halo, tosylate, mesylate and triflate, in particular halo such as iodo.
The reaction between compounds of the formulae (IX) and (X) is conveniently carried out under mild conditions known for the Mitsunobu reaction (Mitsunobu, O. Synthesis 1981, 1), for example in the presence of di (C1-4alkyl)azocarboxylate and triphenylphosphine or 11,11-(azodicarbonyl)dipiperidine and tributylphosphine (Tet. Lett. 34, 1993, 1639-1642) in an inert solvent such as toluene, benzene, tetrahydrofuran or diethylether, in particular toluene. Examples of removable activating groups are tert-butyloxycarbonyl and trifluoroacetyl.
Furthermore the alkoxycarbonyl groups can be removed by hydrolysis of the ester to leave the unprotected amino group and trifluoroacetyl groups can be reduced to 2,2,2-trifluoroethyl.
When R8 is alkoxycarbonyl and R12 a leaving group such as tosylate, mesylate, chloro, bromo or iodo, the compounds of the formula (IX) and (X) can be reacted together to form a compound of the formula (I) or (III), in the presence of a strong base such as sodium hydride, potassium hydride, potassium tert-butoxide, lithium diisopropyl amine or LiN(SiMe3)2, in DMF or an etherial solvent such as diethyl ether or THF, in a temperature range of xe2x88x9278xc2x0 C. to ambient temperature.
Compounds of the formula (IX) wherein p is 1 are conveniently prepared from a compound of the formula (IXA)xe2x80x94see scheme 1. For example by reacting the compound of the formula (IXA) with tosyl or mesyl chloride or using Mitsunobu reagents. Compounds of the formula (IXA) may be formed as shown in scheme 1, from compounds of the formulae (VD) or (IXB).
Compounds of the formula (VD) may be converted to compounds of the formula (IXA) by either sequential treatment with Bu3SnH, ozone and sodium borohydride, (Tet Lett (1987), 28, 53, 67) or, hydrogenation with Pd/C (or other catalysts to the RCH2CH2NO2) followed by the Nef reaction [conditions for the Nef reaction include aqueous TiCl3, or 30% H2O2/K2CO3 (Nef reaction is detailed in March, Advanced Organic Chemistry)] and sodium borohydride reduction, to give the aldehyde (RCH2CHO).
Compounds of the formula (IXB) are prepared by reacting a compound of the formula (IXC) with a compound of the formula CH2xe2x95x90CHM, wherein M is trialkyltin, magnesium halide or di(alkoxy)borane/weak base (for example potassium or caesium carbonate) in the presence of a catalytic amount of palladium (0). The magnesium and tin reactions are conveniently performed in anhydrous THF. The compound of the formula (IXB) is conveniently converted to the alcohol (IXA) by reacting it with catechol borane followed by treatment with hydrogen peroxide. 
Compounds of the formula (X) are conveniently prepared from compounds of the formula H2Nxe2x80x94(CH(R3))qxe2x80x94Bxe2x80x94R7 wherein B and R7 are as hereinabove defined. R8 may be introduced using a similar reaction to that of process d) and R11 may be introduced by standard methods known in the amino-protecting group art.
Compounds of the formula NH2(CH(R3))qxe2x80x94Bxe2x80x94R7 are generally known in the art or an be prepared from related compounds having other functional groups in place of the amino group. For example, a compound of the formula NO2(CH(R3))qxe2x80x94Bxe2x80x94R7 may be reduced to the amino group.
The compounds of the formula (XIa) and (XIb) may be reduced under standard conditions known in the art for the reduction of olefins, and acetylenes, for example, catalytic hydrogenation using Raney nickel, platinum metal or its oxide, rhodium, zinc oxide, palladium-on-charcoal or Wilkinson""s catalyst [RhCl(Ph3P)3] as the catalyst. When halo groups are present in the compounds of the formula (XIa) or (XIb), Wilkinson""s catalyst is preferred.
Catalyst hydrogenation is conveniently carried out in the temperature range 0xc2x0 C. to 150xc2x0 C., but preferably at ambient temperature at slightly above atmospheric pressure, unless the double bond is highly substituted in which case higher temperatures and pressure may be required, or Wilkinson""s catalyst in which case a temperature of approximately 50xc2x0 C. and pressure of approximately 50 atmospheres are preferable.
Compounds of the formula (XIa) can be prepared using a Wittig or Horner-Emmons reagent. For example, compounds of the formula (XIa1) and (XIa2) may be reacted together in an inert solvent such as hexane, tetrahydrofuran or diethyl ether in a temperature range of xe2x88x9278xc2x0 C. to ambient. 
wherein R13xe2x80x94R15 are independently C1-6alkyl or optionally substituted phenyl.
Preferably R13xe2x80x94R15 are all the same. In particular R13xe2x80x94R15 are all phenyl.
The compounds of the formula (XIa2) are rarely isolatable and usually prepared in situ by deprotonating a compound of the formula (XIa3) (scheme 2). Deprotonation is usually carried out in an inert solvent such as tetrahydrofuran or diethyl ether, in a temperature range of xe2x88x9278xc2x0 C. to ambient, in the presence of a strong base. Examples of strong bases are lithium hexamethyldisilylamide, CH3SOCH2xe2x80x94Na+ and butyl lithium.
Compounds of the formula (XIa3) may be prepared by reacting a compound of the formula (XIa4) with a compound of the formula (XIa5) (scheme 2). Suitable values for L11 include halogen, such as chloro, bromo or iodo. Typically an inert solvent such as acetonitrile, diethyl ether, tetrahydrofuran or toluene is used and a temperature range of 50xc2x0 C. or 120xc2x0 C. The compounds of the formula (XIa4) may be known or prepared from another compound of the formula (XIa4) or a compound of the formula Dxe2x80x94CHO wherein D is as hereinabove defined. For example the compound of the formula Dxe2x80x94CHO may be reduced to a compound of the formula (XIa4) wherein L11 is hydroxy. A compound of the formula (XIa4), wherein L11 is hydroxy, may then be converted to a compound of the formula (XIa4) wherein L11 is bromo by, for example, bromonating with tetrabromomethane/triphenylphosphine or tribromophosphine. 
wherein D, R13-R15 and L11 are as hereinabove defined.
Alternatively, compounds of the formula (XIa) can be prepared by dehydrating a compound related to a compound of the formula (I) or (III) in which X is xe2x80x94CH(OH)CH2xe2x80x94. Dehydration is conveniently carried out using standard methods known in the art, for example, at elevated temperatures in the presence of sulphuric acid, phosphoric acid or aluminium oxide. Alternatively, the hydroxy group may be converted to a bromo group. The alkene can then be formed by treatment with a strong base such as sodium hydride or LDA.
The compounds in which X is xe2x80x94CH(OH)CH2xe2x80x94 may be prepared by reacting a compound of the formula (XIa1) with Dxe2x80x94CH2xe2x80x94 in the form of a zinc or Grignard reagent. Reaction conditions for these common reactions are known in the art. For example by reacting DCH2X8, wherein X8 is a leaving group such as bromo or iodo, with zinc or magnesium as appropriate in an inert solvent such as ether or THF, in a temperature range of 0xc2x0 C. to reflux. The reaction can be initiated by the introduction of iodine or 1,2-dibromomethane if necessary. When ester groups are present in one or other of the reagents, the zinc reaction is preferred.
Compounds of the formula (XIb) are conveniently prepared by reacting a compound of the formula (XIb1) with a Dxe2x80x94X7Cu(I) salt, wherein X7 is a leaving group under conditions known for the Heck reaction: 
The reaction is performed in the presence of palladium(0) catalyst, such as Pd(PPh3)4 or Pd(OAc)2 which form the active Pd(0) catalyst in situ. Other palladium(0) catalysts are known in the art. Suitable leaving groups may be chosen from bromo, chloro, iodo, trifluoromethylsulphonyloxy or fluorosulphonate.
Compounds of the formula (XIb1) can be formed by reacting a compound of the formula (XIb2) with a compound of the formula CHxe2x89xa1Cxe2x80x94TMS or CHxe2x89xa1CC(Me)2OH: 
wherein TMS is trimethylsilyl and X10 is a leaving group. This coupling reaction is performed in an inert solvent, such as dimethylformamide, tetrahydrofuran or NMP, in the presence of palladium(0), copper (I) in the form of a salt such as the halide or triflate, and a base such as triethylamine, tributylamine, 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) or potassium acetate.
It is not always convenient to form the acetylene lower link in intermediates containing the upper xe2x80x94Z1xe2x80x94Bxe2x80x94R7 group, because certain groups may be sensitive to the reaction conditions. It may therefore be more appropriate to form the acetylene link prior to the introduction of the upper link using processes and intermediates related to those of processes a), b), e), m), n), o), p), q), or r) and their precursor processes.
The hydrogenation of the compound of the formulae (XII) is performed under standard conditions known in the art. Examples of the catalytic hydrogenation agents are given above in the discussion of the reduction of compounds of the formula (XIa) and (XIb).
Compounds of the formula (XII) may be formed by reacting a compound of the formula Dxe2x80x94CHO or 
with the appropriate zinc or Grignard reagent [R7xe2x80x94Z7xe2x80x94Axe2x88x92 and Dxe2x88x92 respectively] under conditions known in the art for these reactions.
Compounds of the formulae (XIII) and X3-D are conveniently reacted together in a polar aprotic solvent such as dimethylformamide, tetrahydrofuran or NMP in the presence of palladium(0) or nickel(O) as catalyst.
The reaction between the compound of the formula (XIV) and the compound of the formula X5-D is conveniently a copper mediated oxygen-arylation reaction. The reaction is carried out in an inert solvent such as dimethylformamide or N-methylpyrrolidone (NMP) in the present of a Cu(1)X6 salt and a weak base such as potassium carbonate or caesium carbonate. The reaction is normally carried out in the temperature range of 80-250xc2x0 C. Preferably the leaving group is iodo or bromo.
Compounds of the formulae (XV) and X7CH2D are reacted together in the presence of a base under similar reaction conditions to those described above for the reaction between compounds of the formulae (V) and (VI). Preferably X7 is bromo. Compounds of the formulae (XV) and Dxe2x80x94CHO are conveniently reacted together in an alcohol such as ethanol or isopropanol, in the presence of NaCNBH3 and acetic acid or, alternatively, hydrogenated in the presence of palladium-on-carbon.
Compounds of the formula (XV) may be prepared by reducing the related nitro compound.
The ether-forming reaction between compounds of the formulae L1xe2x80x94CH2D and (XVI) is typically performed in an inert solvent such as acetone or DMF, in a temperature range of ambient to 60xc2x0 C., in the presence of a mild base. Suitable values for L1 include tosylate, mesylate, triflate and halo, for example chloro or bromo. When L1 is bromo, the reaction may, for example, be performed in DMF, at ambient temperature in the presence of a base such as potassium carbonate. When L1 is hydroxy, the Mitsunobu reaction may be used (O. Synthesis, 1981, 1). For example performing the reaction in tetrahydrofuran or toluene in the presence of diethyl azodicarboxylate and triphenylphosphine.
The compounds of the formula L1xe2x80x94CH2xe2x80x94D and (XVI) may alternatively be reacted together using a phase transfer system.
The compounds of the formula (XVII) and R4X8 may be reacted together in an aprotic solvent such as DMF in the presence of a base such as sodium carbonate or sodium hydride. Suitable values for X8 are halo, tosylate, mesylate and triflate, in particular halo such as iodo.
Compounds of the formula (XVIII) are conveniently reduced with lithium aluminium hydride or a borane, under standard conditions known in the art. Compounds of the formula (XVIII) may be formed as shown in Scheme 1. The compound of the formula (VC) is hydrolysed with an aqueous acid or base or basic peroxide, for example aqueous hydrochloric acid, sodium hydroxide or hydrogen peroxide, in a temperature range of 0 to 100xc2x0 C. Carboxylic acid (XVIIIA) may then be reacted with an amine of the formula R7xe2x80x94Bxe2x80x94NHR8 to give the compound of the formula (XVIII) under conditions known in the art for the formation of amides. For examples see pages 972-976 of xe2x80x98Larockxe2x80x94Comprehensive Organic Transformationsxe2x80x99; VCH: New York, 1989:
Compounds of the formula (XIXa) are conveniently prepared by reacting together compounds of the formulae (XIXa1) and (XIXa2) under conditions known for the Wittig or Emmons-Horner reaction. 
wherein p and q are independently 0 or 1, provided that p and q are not both 1.
For example, under similar conditions to those described above for the reaction between compounds of the formulae (XIa1) and (XIa2).
The compounds of the formula (XIXa2) are rarely isolatable and usually prepared in situ by deprotonating a compound of the formula (XIXa3) (scheme 3). Deprotonation is usually carried out as described for the compounds of the formula (XIa3).
Compounds of the formula (XIXa3) may be prepared by reacting a compound of the formula (XIXa4) with a compound of the formula (XIXa5) (scheme 3). Suitable values for X11 include halogen, such as chloro, bromo or iodo. Typically an inert solvent such as acetonitrile, diethyl ether, tetrahydrofuran or toluene is used and a temperature range of 50xc2x0 C. to 120xc2x0 C. The compounds of the formula (XIXa4) may be known or prepared from another compound of the formula (XIXa4) or a compound of the formula (XIXa6): 
wherein B, R3, R7 and q are as hereinabove defined. For example the compound of the formula (XIXa6) may be reduced to a compound of the formula (XIXa4) wherein X11 is hydroxy. A compound of the formula (XIXa4), wherein X11 is hydroxy, may then be converted to a compound of the formula (XIXa4) wherein X11 is bromo by, for example, bromonating with tetrabromomethane/triphenylphosphine or tribromophosphine. 
wherein B, R3, R7, R13-R15, p, q and X11 are as hereinabove defined.
Alternatively compounds of the formula (XIXa) can be prepared by dehydrating a compound of the formula (XIXa7). 
wherein A, B, D, X, p, q, R3 and R7 are as hereinabove defined. Dehydration is conveniently carried out using standard methods known in the art, for example, at elevated temperatures in the presence of sulphuric acid, phosphoric acid or aluminium oxide. Alternatively, the hydroxy group may be converted to a better leaving group, such as tosylate which can then be converted to bromo. The alkene can then be formed by treatment with a strong base such as sodium hydride or LDA.
Compounds of the formula (XIXa7) can be prepared by reacting together compounds of the formula R7xe2x80x94Bxe2x80x94[CH(R3)]q CH(R3) in the form of a zinc or Grignard reagent and (XIXa8). 
Standard conditions for the preparation of zinc or Grignard reagents are known in the art.
Compounds of the formula (XIXb) may be prepared by reacting a R7xe2x80x94Bxe2x80x94X12 Cu(I) salt with a compound of the formula (XIXb1): 
under conditions described above for the xe2x80x98Heck reactionxe2x80x99, wherein D, R3 and A are as hereinabove defined and p is 0 or 1 and X12 is a leaving group.
Compounds of the formula (XIXb1) may be prepared by reacting together compounds of the formulae TMSxe2x80x94Cxe2x89xa1CH or CHxe2x89xa1CC(Me)2OH and (XIXb2): 
wherein A, D, X, R3, X15 and p are as hereinabove defined, under Heck conditions. For example, by performing the reaction in an inert solvent, such as dimethylformamide, tetrahydrofuran or NMP, in the presence of palladium (0), copper (I) in the form of a salt such as the halide or triflate, and a base such as triethylamine, tributylamine, 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) or potassium acetate.
Compounds of the formula (XX) are reduced by standard methods known in the art for the reduction of xcex1,xcex2-unsaturated ketones, without affecting ring B. For example, the double bond may be hydrogenated catalytically using Wilkinson""s catalyst and then the ketone group reduced, if appropriate, by forming the tosyl hydrazone and reducing with sodium borohydride.
The compounds of the formula (XX) are conveniently prepared by reacting a compound of the formula (XXA) with a compound of the formula (XXB): 
The reaction between the compounds of the formula (XXA) and (XXB) is conveniently carried out in the presence of a base, for example, lithium hydroxide or potassium tert-butoxide in an organic solvent such as alcohol, for example, methanol.
The reaction between the compounds of the formulae (XXI) and (XXII) is conveniently performed under standard conditions known in the art. Suitable leaving groups include halo, for example, chloro, bromo or iodo, and tosylate and mesylate.
In general the reaction is performed in an inert solvent such as hexane, tetrahydrofuran or ethyl ether, in a temperature range of xe2x88x92100xc2x0 C. to ambient temperature, in the presence of a strong base such as butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide (LDA) or lithium hexamethyldisilylamide, preferably in the presence of a hindered base such as LDA or lithium hexamethyldisilylazide. For example wherein the leaving group is bromo, in in the presence of LDA at 30xc2x0 C.
Compounds of the formula HP1xe2x80x94Bxe2x80x94R7 and (XXIII) are conveniently reacted together in the presence of a base in a dipolar aprotic solvent such as DMF. When the Mitsunobu reaction is used, no base is necessary. Otherwise the reaction is conveniently performed in the presence of a base. For example when P is sulphur, a suitable base is potassium carbonate and when P is oxygen, a suitable base is sodium hydride.
Suitable values for X13 include halo, tosylate, mesylate or hydroxy activated with triphenylphosphine/diethylazodicarboxylate or other Mitsunobu reagents.
The compound of the formula (XXIII) can be prepared from the related compound in which X13 is hydroxy. For example by reacting the hydroxy compound with tosyl or mesyl chloride in the presence of a base such as triethylamine.
The reaction between compounds of the formulae X14xe2x80x94Bxe2x80x94R7 and (XXIV) is conveniently carried out in an inert polar aprotic solvent such as dimethylformamide or NMP in a temperature range of 80-210xc2x0 C.
Suitable values for X14 include halo and tosyl.
When P is sulphur, the compound of the formula (XXIV), can be prepared by reacting a compound of the formula (XXIII) with sodium sulphide in the presence of zinc/hydrochloric acid, triphenylphosphine/water or aqueous base in a temperature range of 20-100xc2x0 C.
The compounds of the formulae (XXIII), (XXIII) in which X13 is hydroxy and (XXIV) can be prepared using processes for the formation of the lower linking group xe2x80x94Xxe2x80x94 as described hereinabove, from appropriate starting materials.
The reaction between compounds of the formulae (XXV) and (VI) is conveniently carried out under mild conditions known for the Mitsunobu reaction (Mitsunobu, O. Synthesis 1981, 1), for example in the presence of di (C1-4alkyl)azocarboxylate and triphenylphosphine or 11,11-(azodicarbonyl)dipiperidine and tributylphosphine (Tet. Lett. 34, 1993, 1639-1642) in an inert solvent such as toluene, benzene, tetrahydrofuran or diethylether, in particular toluene. Examples of removable activating groups are tert-butyloxycarbonyl and trifluoroacetyl.
Furthermore the alkoxycarbonyl groups can be removed by hydrolysis of the ester to leave the unprotected amino group and trifluoroacetyl groups reduced to 2,2,2-trifluoroethyl.
When R8 is alkoxycarbonyl and X1 a leaving group such as tosylate, mesylate, chloro, bromo or iodo, the compounds of the formula (XXV) and (VI) can be reacted together to form a compound of the formula (I) or (I), in the presence of a strong base such as sodium hydride, potassium hydride, potassium tert-butoxide, lithium diisopropyl amine or LiN(SiMe3)2, in DMF or an etherial solvent such as diethyl ether or THF, in a temperature range of xe2x88x9278xc2x0 C. to ambient temperature.
The compounds of the formula (XXV) may be prepared as shown in Scheme 4
Compounds of the formula (XXVA) can be converted to a compound of the formula (XXV) by reacting (XXVA) with KCNO and tert-butanol in a polar aprotic solvent such as DMF or NMP, with a catalytic amount of pallaidum (0), in a temperature range of 80-200xc2x0 C.
Compounds of the formula (XXVB) are conveniently reacted with (PhO)2PON3 in a temperature range of 0-20xc2x0 C., followed by tert-butanol in a temperature range of 20-100xc2x0 C.
Compounds of the formula (XXVC) can be reduced to the amine with reagents such as zinc/hydrochloric acid, iron/acetic acid, tin (III) chloride, titanium (IV) chloride, or by catalytic hydrogenation. The amine can then be protected with tert-butoxycarbonyl to give a compound of the formula (XXV).
The compounds of the formulae (IVa1), (IVb1), (V), (VA), (VB), (VE), (IXC), (XIXa1), (XIXb2), (XIXa7), (XXA), (XXI), (XXIII), (XXIV), (XXVA), (XXVB) and (XXVC) can be prepared using processes for the formation of the lower linking group xe2x80x94Xxe2x80x94 as described hereinabove, from appropriate starting materials. Similarly, compounds of the formulae (XIa1), (XIa2), (XIV), (XIV), (XV) and the related nitro compound, (XIV) and the zinc or Gignard reagent used in the preparation of compounds of the formula (XII) can be prepared using processes for the formation of the xe2x80x94Zxe2x80x94Bxe2x80x94R7 group as described hereinabove, from appropriate starting materials.
The order in which the upper and lower links are constructed will depend upon the individual substitution patterns and the compatibility of functional groups with the reaction conditions.
The compounds of the formula (VII) may be prepared using processes a), b), d)-r) from the appropriate starting material wherein R7 is replaced with R10.
The compounds of the formula (VIII) or (XVII) may be prepared by using any one of processes a), b), c), e)-r) from the appropriate starting materials wherein R8 is hydrogen.
The compounds of the formulae (VI) are generally known in the art or can be made by methods analogous to or similar to those used in the examples or those known in the art for related compounds.
It is also possible to synthesise certain intermediates and even protected compounds using primarly ring synthesis. Here, reference is made to the compendium xe2x80x98The Chemistry of Heterocyclic Compoundsxe2x80x99 E. C. Taylor and A. Weissberger (published by John Wiley and Sons) and xe2x80x98Comprehensive Heterocyclic Chemistryxe2x80x99, A. R. Katritby and C. W. Rees (published by Pergamon Press).
Optional substituents may be converted into other optional substituents. For example an alkylthio group may be oxidised to an alkylsulphinyl or alkysulphonyl group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, or a bromo group converted to an alkylthio group.
Various substituents may be introduced into compounds of the formulae (I) and (III) and intermediates in the preparation of compounds of the formulae (I) and (III), when appropriate, using standard methods known in the art. For example, an acyl group or alkyl to group may be introduced into an activated benzene ring using Friedel-Crafts reactions, a formyl group by formylation with titanium tetrachloride and dichloromethyl ethyl ether, a nitro group by nitration with concentrated nitric acid concentrated sulphuric acid and bromine by bromination with bromine or tetra(n-butyl)ammonium tribromide.
It will be appreciated that, in certain steps in the reaction sequence to compounds of the formula (I), it will be necessary to protect certain functional groups in intermediates in order to prevent side reactions. Deprotection may be carried out at a convenient stage in the reaction sequence once protection is no longer required.
As stated hereinbefore compounds of the formula (I) are antagonists of the pain enhancing effects of E-type prostaglandins and of value in the relief of pain which, for example, accompanies inflammatory conditions such as rheumatoid arthritis and osteoarthritis. Certain properties of the compounds may be demonstrated using the test procedures set out below:
(a) an in-vitro guinea pig ileum assay which assesses the inhibitory properties of a test compound against PGE2-induced contractions of the ileum; ileum was immersed in oxygenated Krebs solution containing indomethacin (4 xcexcg/ml) and atropine (1 xcexcM) and which was maintained at 37xc2x0 C.; the ileum was subject to a tension of 1 g; a control dose response curve for PGE2-induced contraction of the ileum was obtained; test compound (dissolved in dimethylsulphoxide) was added to the Krebs solution and a dose response curve for the PGE2-induced contraction of the ileum in the presence of the test compound was obtained; the pA2 value for the test compound was calculated;
(b) an in-vivo assay in mice which assesses the inhibitory properties of a test compound against abdominal constriction response induced by the intraperitoneal administration of a noxious agent such as dilute acetic acid or phenylbenzoquinone (hereinafter PBQ) using the procedure disclosed in European Patent Application No. 0218077.
Although the pharmacological properties of the compounds of the formula I vary with structural change as expected, in general activity possessed by compounds of the formula I may be demonstrated at the following concentrations or doses in one or more of the above-mentioned Tests (a) and (b):
Test (a): pA2 greater than 5.3;
Test (b): ED30 in the range, for example, 0.01-100 mg/kg orally.
No overt toxicity or other untoward effects were noted in Test (b) when compounds of the formula I are administered at several multiples of their minimum inhibitory dose. Prostaglandin receptors and in particular receptors for PGE2 have been tentatively characterised by Kennedy et al. (Advances in Prostaglandin, Thromboxane and Leukotriene Research, 1983, 11, 327). The known PGE2 antagonist SC-19220 blocks the effect of PGE2 on some tissues such as guinea pig ileum or dog fundus but not on other tissues such as the cat trachea or chick ileum. Those tissues which did possess SC-19220 sensitive mediated effects were said to possess EP1 receptors. Based on this compounds of the present invention, possessing activity in Test (a), are EP1 antagonists.
According to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) or an in-vivo hydrolysable ester thereof or an amide thereof, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel, spray or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository or rectal spray; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients.
The amount of active ingredient (that is a compound of the formula (I) or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
According to a further feature of the invention there is provided a compound of the formula (1) or an in-vivo hydrolysable ester or amide or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the animal (including human) body by therapy.
According to a further feature of the invention there is provided the use of a compound of the formula I, or an in-vivo hydrolysable ester or amide or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament for use in the relief of pain in the animal (including human) body.
According to a further feature of the invention there is provided a method for the relief of pain in the animal (including human) body in need of such treatment which comprises administering to said body an effective amount of a compound of the formula I, or an in-vivo hydrolysable ester or amide or a pharmaceutically-acceptable salt thereof.
As mentioned above, a compound of the formula (I) is useful in treating the pain which, for example, accompanies inflammatory conditions such as rheumatoid arthritis and osteoarthritis. In using a compound of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.05 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg to 25 mg per kg body weight will be used.
Although the compounds of the formula (I) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to antagonise the effects of PGE2 at the EP1 receptor, based on test a). Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
By virtue of their ability to relieve pain, the compounds of the formula I are of value in the treatment of certain inflammatory and non-inflammatory diseases which are currently treated with a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of a compound of the formula I with a NSAID can result in a reduction of the quantity of the latter agent needed to produce a therapeutic effect. Thereby the likelihood of adverse side-effects from the NSAID such as gastrointestinal effects are reduced. Thus according to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or an in-vivo hydrolysable ester or amide or pharmaceutically-acceptable salt thereof, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent, and a pharmaceutically-acceptable diluent or carrier.
The compounds of the invention may also be used with other anti-inflammatory agents such as an inhibitor of the enzyme 5-lipoxygenase (such as those disclosed in European Patent Applications Nos. 0351194, 0375368, 0375404, 0375452, 037547, 0381375, 0385662, 0385663, 0385679, 0385680).
The compounds of the formula (I) may also be used in the treatment of conditions such as rheumatoid arthritis in combination with antiarthritic agents such as gold, methotrexate, steroids and penicillinamine, and in conditions such as osteoarthritis in combination with steroids.
The compounds of the present invention may also be administered in degradative diseases, for example osteoarthritis, with chondroprotective, anti-degradative and/or reparative agents such as Diacerhein, hyaluronic acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril.
The compositions of the invention may in addition contain one or more other therapeutic or prophylactic agents known to be of value for the treatment of pain. Thus for example, a known opiate pain-killer (such as dextropropoxyphene, dehydrocodeine or codeine) or an antagonist of other pain or inflammation mediators, such as bradykinin, takykinin and calcitonin gene related peptides (CGRP), or an alpha2-adrenoceptor agonist, a GABAB receptor agonist, a calcium channel blocker, a sodium channel blocker, a CCKB receptor antagonist, a neurokinin antagonist or an antagonist and modulator of the action of glutamate at the NMDA receptor may usefully also be present in a pharmaceutical composition of the invention.
The compounds of the present invention may also be administered in bone diseases such as osteoporosis with calcitonin and bisphosphonates.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:
(i) evaporations were carried out by rotary evaporations in vacuo and work-up procedures were carried out after removal or residual solids by filtration;
(ii) yields are given for illustration only and are not necessarily the maximum attainable;
(iii) the end-products of the formula I have satisfactory microanalysis and their structures were generally confirmed by NMR and mass spectral techniques;
(iv) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, infra-red (IR) or NMR analysis;
(v) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after recrystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
(vi) the following abbreviations have been used: